The heart is the center of a person's circulatory system. It includes an electromechanical system performing two major pumping functions. The left portions of the heart draw oxygenated blood from the lungs and pump it to the organs of the body to provide the organs with their metabolic needs for oxygen. The right portions of the heart draw deoxygenated blood from the organs and pump it into the lungs where the blood gets oxygenated. The body's metabolic need for oxygen increases with the body's physical activity level. The pumping functions are accomplished by contractions of the myocardium (heart muscles). In a normal heart, the sinoatrial node, the heart's natural pacemaker, generates electrical impulses, known as action potentials, that propagate through an electrical conduction system to various regions of the heart to excite myocardial tissues in these regions. Coordinated delays in the propagations of the action potentials in a normal electrical conduction system cause the various regions of the heart to contract in synchrony such that the pumping functions are performed efficiently.
A blocked or otherwise damaged electrical conduction system causes the myocardium to contract at a rhythm that is too slow, too fast, and/or irregular. Such an abnormal rhythm is generally known as arrhythmia. Arrhythmia reduces the heart's pumping efficiency and hence, diminishes the blood flow to the body. A deteriorated myocardium has decreased contractility, also resulting in diminished blood flow. A heart failure patient usually suffers from both a damaged electrical conduction system and a deteriorated myocardium. The diminished blood flow results in insufficient blood supply to various body organs, preventing these organs to function properly and causing various symptoms. For example, in a patient suffering acute decompensated heart failure, an insufficient blood supply to the kidneys results in fluid retention and edema in the lungs and peripheral parts of the body, a condition referred to as decompensation. Without effective treatment, acute decompensated heart failure cause rapid deterioration of the cardiovascular and general health and significantly shortened life expectancy. Treatments for arrhythmias and heart failure include, but are not limited to, electrical therapy such as pacing and defibrillation therapies, drug therapies, and biological therapies including gene-based therapies.
Gene-based therapies include the delivery of therapeutic genes to targeted cells and in some cases, the use of regulatable systems. For gene-based therapies which require expression of sequences in vectors, a promoter is linked to the sequence to be expressed. Strong viral promoters can drive a high level of expression in a wide range of tissues and cells, however, constitutive expression is an open loop system and the encoded gene product may induce cellular toxicity or tolerance, or down regulation of expression through negative feedback.
One strategy to regulate the expression of target genes employs endogenous regulatable elements, and another strategy employs exogenous inducible gene expression systems. For example, heat-shock-induced loci have been used to regulate the expression of a heterologous gene in mammalian cells (Wurm et al., Proc. Natl. Acad. Sci. USA, 83:5414 (1986); Bovenberg et al., Mol. Cell Endocrinol., 74:45 (1990)), and hypoxia-inducible cis-acting sequences from the erythropoietin gene allow a transcriptional response by hypoxia-inducible transcription factor (HIF-I) (Wang et al., Curr. Op. Hematol., 3:156 (1996)). However, many regulatable systems based on endogenous promoters suffer from weak induction and high basal expression.
What is needed is a device useful to control expression of gene therapy vectors, e.g., to treat cardiovascular conditions.